The present invention relates to certain novel 1,2-diaminocyclohexane platinum complexes and their use in the treatment of tumors.
Recently, certain platinum complexes have been shown by Rosenberg, et al. and others to be highly active anti-tumor agents (see U.S. Pat. Nos. 4,177,263 and 4,140,707). For example, the complex cis-dichlorodiamineplatinum-II or "cisplatin" is the chemotherapeutic agent of choice in the treatment of many and varied tumors.
There are several drawbacks, however, associated with the use of the platinum complexes to treat tumors. Generally, the platinum complexes have a relatively low solubility in water thereby rendering it difficult to formulate a composition which can effectively deliver the reagent to the site of the tumor in the body.
Moreover, many of the platinum complexes are highly nephrotoxic thereby further restricting their use in the absence of precautionary measures to avoid damage to the kidneys when administered to animals afflicted with tumors.
Recently, considerable activity has centered on the use of 1,2-diaminocyclohexane complexes of platinum as anti-tumor agents. See, for example, U.S. Pat. Nos. 3,892,790; 3,904,663; 4,115,418; 4,140,707; 4,169,846; 4,175,133; 4,228,090 and 4,256,652 and German Offenlegungschrift No. 30 22 917.
Although the complexes described therein possess anti-tumor activity, virtually all are highly insoluble in water and are also relatively highly nephrotoxic.
German Offenlegungschrift No. 30 22 957 describes 1,2-diaminocyclohexane/ascorbate complexes of platinum, useful as anti-tumor agents, which comprise mixtures of complexes having varying ratios of ascorbate ion to platinum. Thus, the publication discloses complexes of the formula: ##STR2## wherein n varies from 1.2 to 1.5. The complexes are described as poorly water soluble.
in the Proceedings for the American Association for Cancer Research, Vol. 23, page 116, 1982, we describe New Platinum Complexes Containing Ascorbate having good aqueous solubility, useful antitumor activity and decreased nephrotoxicity. Two such complexes, one containing Pt, aminoethylpyrrolidine and ascorbate and the second containing Pt, 1,2-diaminocyclohexane, chloride and ascorbate are capable of suppressing the growth of L1210 cells in vivo.
J. Am. Chem. Soc. 1985, 107, 274-276 describes the synthesis of a series of cis-[Pt(RNH.sub.2).sub.2 ] (ascorbate) complexes which are reported to be stable in aqueous or alcoholic solutions and are active in the S180a tumor screen.
We have now found that certain other 1,2-diaminocyclohexane (DACH)-platinum-anion complexes are vastly superior to the ascorbate complexes in being relatively non-nephrotoxic, possessing a high degree of antitumor activity, high water-solubility, and no cross resistance to cis(DACH)-dichlorodiamine platinum II. In particular, we have found that the iminodiacetatocyclohexane platinum (II) complexes have marked in vitro cytotoxic activity, good in vivo activity as a single injection which is significantly enhanced when administered intraperitoneally and significantly less nephrotoxicity than cis-platin.
Especially preferred embodiments of this invention include the mixed isomer DACH-Pt (II) iminodiacetato complexes and the trans-R,R-DACH-Pt (II) mono-iminodiacetato, mono-N-methyl-iminodiacetato, mono-N-hydroxyethyliminodiacetato, mono-N-phenyliminodiacetato, and mono-N-benzyliminodiacetato complexes. These complexes are especially valuable in that they enhance the cytotoxicity without increased host toxicity.
It is an object of the present invention to provide non-nephrotoxic 1,2-diaminocyclohexane (DACH)-platinum-anion complexes containing 1.0 bidentate or 2 monodentate negatively charged organic radicals per molecule of platinum possessing high degrees of anti-tumor activity, high water-solubilities, and no cross resistance to cis-dichlorodiammine platinum II.
It is a further object of the invention to provide a method for the preparation of the platinum complexes.
It is a further object of the invention to provide a method for preparing DACH-platinum-anion complexes containing stoichiometric ratios of anion to platinum.
It is a further object of the invention to provide a pharmaceutical composition particularly adapted for the treatment of animals afflicted with tumors.
It is a further object of the invention to provide a therapeutic method for the treatment of animals afflicted with tumors.